FOXO4
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| Location (UCSC) | Chr X: 71.1 – 71.1 Mb | Chr X: 100.3 – 100.3 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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Forkhead box protein O4 is a protein that in humans is encoded by the FOXO4 gene.[5][6]
Structure and function
FOXO4 is a member of the forkhead family of transcription factors in O subclass, which is characterized by a winged helix domain used for DNA binding. Both PI3K and AKT modify FOXO4 and prevent it from translocating to the nucleus, effectively preventing the transcription of the downstream FOXO targets.
Clinical significance
Associations with longevity
FOXO transcription factors have been shown to be the downstream effector molecules of
FOXO4 can bind with p53 protein to induce cellular senescence.[20] A peptide competing with FOXO4 can act as a senolytic by excluding p53 from the nucleus.[20]
Cancer
Many different kinds of cancers have been observed to contain mutations that promote AKT phosphorylation, and thus the inactivation of FOXOs, effectively preventing proper cell cycle regulation.
In gastric cancers (GC), it has been observed that there were lower levels of FOXO4 mRNA in cancers that had already progressed to invading lymph nodes compared to cancers that remained in situ.[26] When compared to normal tissue, all GC epithelia had lower levels of FOXO4 located in the nucleus, consistent with less FOXO4 effector activity and FOXO4's function as a suppressor of carcinogenic properties. It does this by causing cell cycle arrest between the Go and S phases, preventing cell proliferation, as well as by inhibiting metastasis by downregulating vimentin.[27] These results are consistent with FOXO4 providing a role in inhibiting the epithelia to mesenchymal transition (EMT).
In non-small cell lung carcinoma, there are varying levels of FOXO4 expressed that correspond to how the cancer was staged; worse cases had the lowest amount of FOXO4 while less severe cases had higher levels of FOXO4.
Interactions
- CIC – chromosomal translocation resulting in a fusion CIC-FOXO4 protein is observed in some tumors.[31]
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000184481 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042903 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- S2CID 19965473.
- ^ "FOXO4 forkhead box O4 [ Homo sapiens (human) ]".
- S2CID 1986657.
- S2CID 26488600.
- S2CID 31546098.
- PMID 15987244.
- PMID 16076959.
- S2CID 22561455.
- PMID 17940099.
- PMID 18786403.
- PMID 17604717.
- S2CID 35743203.
- PMID 18832074.
- S2CID 4332206.
- PMID 18765803.
- ^ PMID 28340339.
- S2CID 23093929.
- S2CID 10147415.
- PMID 15805248.
- ^ S2CID 20360440.
- ^ PMID 17254969.
- PMID 21934092.
- PMID 24886657.
- ^ PMID 24935588.
- PMID 18794148.
- PMID 18665269.
- S2CID 211192274.
Further reading
- Borkhardt A, Repp R, Haas OA, Leis T, Harbott J, Kreuder J, Hammermann J, Henn T, Lampert F (1997). "Cloning and characterization of AFX, the gene that fuses to MLL in acute leukemias with a t(X;11)(q13;q23)". Oncogene. 14 (2): 195–202. S2CID 19818372.
- Peters U, Haberhausen G, Kostrzewa M, Nolte D, Müller U (1997). "AFX1 and p54nrb: fine mapping, genomic structure, and exclusion as candidate genes of X-linked dystonia parkinsonism". Hum. Genet. 100 (5–6): 569–72. S2CID 35332593.
- Kops GJ, de Ruiter ND, De Vries-Smits AM, Powell DR, Bos JL, Burgering BM (1999). "Direct control of the Forkhead transcription factor AFX by protein kinase B". Nature. 398 (6728): 630–4. S2CID 4394066.
- Takaishi H, Konishi H, Matsuzaki H, Ono Y, Shirai Y, Saito N, Kitamura T, Ogawa W, Kasuga M, Kikkawa U, Nishizuka Y (1999). "Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B". Proc. Natl. Acad. Sci. U.S.A. 96 (21): 11836–41. PMID 10518537.
- Medema RH, Kops GJ, Bos JL, Burgering BM (2000). "AFX-like Forkhead transcription factors mediate cell-cycle regulation by Ras and PKB through p27kip1". Nature. 404 (6779): 782–7. S2CID 205005804.
- Furuyama T, Nakazawa T, Nakano I, Mori N (2000). "Identification of the differential distribution patterns of mRNAs and consensus binding sequences for mouse DAF-16 homologues". Biochem. J. 349 (Pt 2): 629–34. PMID 10880363.
- Weigelt J, Climent I, Dahlman-Wright K, Wikström M (2000). "1H, 13C and 15N resonance assignments of the DNA binding domain of the human forkhead transcription factor AFX". J. Biomol. NMR. 17 (2): 181–2. S2CID 91193730.
- Nasrin N, Ogg S, Cahill CM, Biggs W, Nui S, Dore J, Calvo D, Shi Y, Ruvkun G, Alexander-Bridges MC (2000). "DAF-16 recruits the CREB-binding protein coactivator complex to the insulin-like growth factor binding protein 1 promoter in HepG2 cells". Proc. Natl. Acad. Sci. U.S.A. 97 (19): 10412–7. PMID 10973497.
- Brownawell AM, Kops GJ, Macara IG, Burgering BM (2001). "Inhibition of nuclear import by protein kinase B (Akt) regulates the subcellular distribution and activity of the forkhead transcription factor AFX". Mol. Cell. Biol. 21 (10): 3534–46. PMID 11313479.
- Weigelt J, Climent I, Dahlman-Wright K, Wikström M (2001). "Solution structure of the DNA binding domain of the human forkhead transcription factor AFX (FOXO4)". Biochemistry. 40 (20): 5861–9. PMID 11352721.
- Schuur ER, Loktev AV, Sharma M, Sun Z, Roth RA, Weigel RJ (2001). "Ligand-dependent interaction of estrogen receptor-alpha with members of the forkhead transcription factor family". J. Biol. Chem. 276 (36): 33554–60. S2CID 11652289.
- De Ruiter ND, Burgering BM, Bos JL (2001). "Regulation of the Forkhead transcription factor AFX by Ral-dependent phosphorylation of threonines 447 and 451". Mol. Cell. Biol. 21 (23): 8225–35. PMID 11689711.
- Tang TT, Dowbenko D, Jackson A, Toney L, Lewin DA, Dent AL, Lasky LA (2002). "The forkhead transcription factor AFX activates apoptosis by induction of the BCL-6 transcriptional repressor". J. Biol. Chem. 277 (16): 14255–65. S2CID 22501049.
- Yang Z, Whelan J, Babb R, Bowen BR (2002). "An mRNA splice variant of the AFX gene with altered transcriptional activity". J. Biol. Chem. 277 (10): 8068–75. S2CID 22605434.
- Kops GJ, Medema RH, Glassford J, Essers MA, Dijkers PF, Coffer PJ, Lam EW, Burgering BM (2002). "Control of cell cycle exit and entry by protein kinase B-regulated forkhead transcription factors". Mol. Cell. Biol. 22 (7): 2025–36. PMID 11884591.
- So CW, Cleary ML (2002). "MLL-AFX requires the transcriptional effector domains of AFX to transform myeloid progenitors and transdominantly interfere with forkhead protein function". Mol. Cell. Biol. 22 (18): 6542–52. PMID 12192052.
- Tang TT, Lasky LA (2003). "The forkhead transcription factor FOXO4 induces the down-regulation of hypoxia-inducible factor 1 alpha by a von Hippel-Lindau protein-independent mechanism". J. Biol. Chem. 278 (32): 30125–35. S2CID 43919271.
- Crossley LJ (2003). "Neutrophil activation by fMLP regulates FOXO (forkhead) transcription factors by multiple pathways, one of which includes the binding of FOXO to the survival factor Mcl-1". J. Leukoc. Biol. 74 (4): 583–92. S2CID 15199594.
External links
- MLLT7+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Overview of all the structural information available in the PDB for UniProt: P98177 (Forkhead box protein O4) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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